Navigating Regulatory Pathways for Pharmabiotics

The PRI, as a neutral and financially independent non-profit association, has developed and applied its Regulatory Strategy since 2013 – Scientific Advice Request dossiers, European regulatory research & intelligence, and Task Group initiatives to provide regulatory insight for its members. Today, the PRI has been identified by European regulatory authorities as a key representative body in the European microbiome/ health industry. Join our Regulatory discussions at the PRI’s Pharmabiotics 2019:

The Office of Vaccines Research and Review (OVRR) in the Center for Biologics Evaluation and Research (CBER) is responsible for regulatory review of Investigational New Drug (IND) applications and Biologics License Applications (BLAs) for preventive vaccines and related biological products, including live microbiome – based products used to prevent, treat, or cure diseases in humans. Through this review process, OVRR ensures that the products are safe, pure and potent. During the IND review process, the amount and type of data changes as drug development progresses. My presentation will highlight the clinical and CMC expectations at each phase of development for microbiome-based products.

LCDR Matthew Steele is a Team Leader in Regulatory Review Branch 1 in the Division of Vaccines and Related Products Applications (DVRPA), in the Office of Vaccines Research and Review (OVRR) at CBER. Additionally, he is a Lieutenant Commander in the United States Public Health Service Commissioned Corps. LCDR Steele has been with the FDA since 2009. During that time he has served as the primary reviewer for numerous pre-IND meetings, INDs, and BLAs. His primary focus has been live microbiome-based products and live biotherapeutic products. He serves as the primary POC for CBER for fecal microbiota transplantation. Prior to joining the Agency, LCDR Steele earned a B.S. in Biology at Salisbury University (Salisbury, MD) and a Ph.D. in Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health (Baltimore, MD). He completed his Ph.D work in the labs of Dr. Cecile Pickart and Dr. Michael Matunis, and wrote his thesis on kinetics of deubiquitinating enzymes.

“Introduction to the Microbiome Therapeutics Innovation Group: Legislative and Regulatory Opportunities to Enhance the U.S. Regulatory, Investment, and Commercial Environment to Accelerate Microbiome Therapeutic Product Development“

The Microbiome Therapeutics Innovation Group (MTIG) is a coalition of companies leading the research and development for U.S. Food and Drug Administration (FDA)-approved microbiome therapeutics and microbiome-based products to address unmet medical needs, improve clinical outcomes, and reduce health care costs. Through a collective voice, the MTIG membership works together to enhance the regulatory, investment, and commercial environment to accelerate microbiome therapeutic product development and enable the field to reach its potential to benefit patients. The human microbiome is a new frontier of medical innovation that has the potential to benefit patients suffering from numerous diseases afflicting millions of patients, and consuming billions of dollars of healthcare resources. Areas of research include infectious diseases, gastrointestinal disorders, cancers, mental or psychological diseases, autoimmune diseases and more. MTIG is committed to working with stakeholders who share in our mission and seek tangible policy and regulatory solutions in the emerging microbiome arena.

Jim Weston is a veteran regulatory affairs and qualityexecutive with a demonstrated ability to spearhead the drug development process by crafting effective regulatory and clinical strategies world-wide, including the US, Canada, Europe (centralized and member states), Australia and Japan. His knowledge of domestic and international regulatory requirements and his close interactions with regulatory authorities has resulted in successful and timely implementation of clinical trial programs and integrated regulatory submissions, including investigational and marketing applications that resulted in the approval of multiple drugs/biologics worldwide. Jim currently heads the regulatory function at Seres Therapeutics, Inc. a company leading the development of microbiome therapeutics. Jim has a BA in Biological Sciences degree from Rutgers College and an MBA from Northeastern University. He is a member of and frequent presenter for many professional organizations, including the Regulatory Affairs Professionals Society, Drug Information Association, Parenteral Drug Association, the Special Operations Medical Association and formerly was the co-chair of the Quality and Regulatory Committee of MassBio.

Stephen Conafay has 35 years of leadership and management experience in government relations, public policy and communications. Mr. Conafay is a lawyer and a decorated Vietnam veteran, served as an infantry platoon leader and was awarded the Silver Star, Bronze Star with Oak Leaf Cluster, the Air Medal and the Army Commendation Medal, among others. As the sole principal at The Conafay Group, Mr. Conafay oversees all client servicing. The Conafay Group is a life-sciences government relations firm based in Washington D.C. that specializes in representing biomedical technologies and therapeutics before the federal government and associated stakeholders. The Conafay Group works with life science companies and organizations to develop and implement government funding and public policy strategies and serves as Washington Counsel and coalition manager for MTIG.

“Putting into Perspective the International Regulatory Initiatives in Food & Pharma”

Regarding the latest developments surrounding food and pharma regulations, it would seem important to clarify the different initiatives and changes relative to living micro-organisms and their consequences for developers. On the pharma side, clarification of the expectations of drug authorities is of the utmost importance. In this presentation, we will address certain key points facing the industry today: medical device status and robust clinical design, among others…

Magali Cordaillat-Simmons earned her PhD in 2005 at Université Descartes – Paris, France, in Cardiovascular Pharmacology. She then worked as a Research Associate at the University of Virginia, VA, USA, where she studied the influence of epigenetics on renin expression. Today, she is the Executive Director for Scientific & Regulatory Affairs at the Pharmabiotic Research Institute (PRI), located in France. The PRI is Europe’s first and only expert regulatory group dedicated to supporting its members in the development and market authorization of Microbiotic Medicinal Products (MMPs). As a non-profit, Pro-industry organization, the PRI is uniquely positioned to both be a trusted point of contact for the European regulatory authorities, as well as an agile and neutral partner for the Microbiome & Health industries. Dr. Cordaillat-Simmons currently supervises the Association’s analysis of the European Pharmaceutical Legislation as well as the PRI’s unique regulatory intelligence strategy so that “Microbiotic Medicinal Products” may become a therapeutic reality for European patients.

“Probiotics and the CODEX Initiative: History, Current Situation and Future Perspectives.”

An expert consultation group, called together by the Food and Agriculture Organization/World Health Organization (FAO/WHO) was held in 2001 on the “Evaluation of health and nutritional properties of probiotics in food, including powdered milk with live lactic acid bacteria”. The importance of probiotics to human and animal health was recognized and many aspects of the use of probiotic foods and their production were discussed. The working group intended to overcome a lack of international agreements on how to define and label probiotics and how to assess their safety and efficacy, involving aspects of production, dose and target population. Eighteen years later there is still no consensus on many of these aspects. The ban of the word ‘probiotic’ in Europe, because of the definition proposed in 2001, is only one of the pending issues which requires a solution. The lack of harmonization in industry practice and legislation is confusing for regulators, industry, and even for the consumer. Many countries, led by Argentina, recognize the need and opportunity for development of a Codex Alimentarius guidance or standard to more clearly define the required characteristics of safe and efficacious probiotics, and ensure the same level of quality and manufacturing requirements for all operators on the market. The Codex Alimentarius international food standards and guidelines contribute to the safety, quality and fairness of international food trade. While being recommendations for voluntary application by members, Codex standards serve in many cases as a basis for legislation. The establishment of eligibility criteria and an organized framework for the production of probiotic products will provide a guideline to global regulatory agencies, authorities, consumers and industry, allowing to build probiotics-focused regulations and help in a better understanding of probiotics and their health benefits. In the presentation the past, current and future perspective of this initiative will be illustrated.

Dr. ir. Bart Degeest graduated in 1995 as an engineer in cell- and gene-biotechnology at the Vrije Universiteit Brussel (Belgium) and obtained in 2001 a PhD in Applied Biological Sciences at the same university with a research project on the composition and production of exopolysaccharides by Streptococcus thermophilus. After his PhD period Bart joined the company Yakult as Science manager, taking care of research projects and scientific communication in the field of probiotics. He is now managing director of Yakult Belgium & France and very much involved in, besides the ongoing research, the activities of working groups and organisations as FEVIA, ILSI, IDF, IPA-EU, IPA-global and CODEX. The objective of these organisations is often related to a better definition of probiotics, their safety, their production process and, in a European context, the re-introduction of the term ‘probiotic’.

Facing the emergence of difficult-to-threat bacterial infections, the perspective of using the anti-bacterial potential of bacteriophages has re-gained a significant interest in many countries. In Western countries , bacteriophages are not of common use, and, in turns, do not have a specific regulatory framework, for both the use and the production of the phages.
From a pharmaceutical classification point of view, phages fall in the categories of anti-infectious products and of biological products, given the intended use and their live nature. In addition, the compliance to the Good Manufacture Practices (GMP) is a requirement for any medicinal product.
During the EU-funded PhagoBurn’s project, we solved the challenges of 1) producing two cocktails of lytic bacteriophages in compliance with the GMPs, 2) performing a phase I-II clinical trial on burn patients suffering from E. coli or P. aeruginosa infections. The rich interactions with the national authorities in 3 countries (France, Belgium, and Switzerland) during PhagoBurn’s experience, and in other phage-therapy projects, have shown the interest of the authorities to investigate the potential of phage therapy. Accordingly, the working frame for new development is better determined.

As head of R&D for Clean Cells, Laurent Bretaudeau contributed to the growth of the company by implementing innovative quality control methods and developing the manufacturing of biological products under Good Manufacturing Production (GMP) compliance. He supervised the GMP production of bacteriophages for the phage therapy program PhagoBurn. During this European project, bacteriophages were used in a clinical trial with infected burn patients. Laurent had a major contribution in the regulatory process through the communication with the health authorities during the PhagoBurn project, and now in other projects based on phage therapy.

“Keeping Up-to-Date with Guidelines to Speed up Your Regulatory Submissions”

Many guidelines affecting the development and manufacturing of Live Biotherapeutic Products (LBPs) are currently in draft form or have recently been published. Working on the changes in advance of publication is crucial: firstly, to be ready once applicable and second, to mitigate risk. This presentation will focus on some of the most important upcoming guidelines including:

EU n°536/2014 – : Good Manufacturing Practices for IMPs for Human use– Draft Dec 2017-
There is no longer any doubt of the requirements for IMP (Investigational Medicinal Products), such as Traceability of changes, Qualification and the Release Chain.

European Pharmacopea – LBPs (Live Biotherapeutic for Human Use) – Dec 2018-
The requirements for LBPs regarding traceability of the strain from the Research, “Sterile” media and control of the Product are now clear.

Annex 1 – GMP- : Manufacture of Sterile Medicinal Products – Draft Dec 2017-
Assuming that the Annex 1-GMP concerns only sterile products is an oversight. The principles of this guideline should be followed to control the risk of contamination.

Frederique acquired a multi-disciplinary vision of the Drug Development, from Research to Regulatory submission after spending over 15 years experience in Pharma/Biotech companies. Following her graduation as Pharmacyst, she moved into a French CDMO, producing and developing solid forms for the commercial market. She graduated as an “Engineer in Biotechnology” and became Head of QA – QP Deputy in a Swiss company for sterile products in clinical phases. Then, Frederique was responsible for the Pharmaceutical chain as Quality Director in a UK start-up developing LBPs. Frederique founded 5QBD-Biotech (Quality Business Development) to secure and speed up any Drug Development and Manufacturing process.

Recent advances of research in microbial analytics have led to the development of next-generation flow cytometry protocols. These innovative approaches are particularly well suited for global and multiparametric analysis of probiotics; and they bring efficient solutions to the numerous limitations of classical microbiology and other analytical methods. In this context, standardization of these new methods is a critical requirement for their harmonized implementation and application. In 2015, the International Standardization Organization (ISO) and the International Dairy Federation (IDF) published a standard on flow cytometry validated for the use in quantification of Lactic Acid Bacteria (LAB) and probiotic strains (ISO 19344:2015 | IDF 232). This first ISO/IDF standard includes three individual protocols, each one determining different viability parameter. Equivalence between the three staining protocols has been demonstrated. ISO/IDF has recently initiated another flow cytometry standardization project aiming at specific quantification and viability assessment of multiple microbial species in LAB and probiotic products. This presentation will give an overview of the current situation regarding standardization of flow cytometry methods applied to beneficial microbes as well as future perspective.

Dr Pierre Burguière is a microbiologist with 15+ years of experience. He’s the founder and CEO of AMA Research Solutions, a biotech company servicing in Flow Cytometry to develop innovative solutions for the analysis of beneficial microbes for health (i.e. live biotherapeutics) and microbiotas. Dr Burguière is also Delegate for France on the Standing Committee for Analytical Methods for Dairy Microorganisms (SCAMDM) of the International Dairy Federation, member of the U.S. Pharmacopeial Convention Expert Panel on Probiotics, and member of the Board of Directors of the French Association for Cytometry.